Concomitant MEK and Cyclin Gene Alterations: Implications for Response to Targeted Therapeutics.

Purpose Cyclin and MAPK/MEK-related gene alterations are implicated in cell-cycle progression and cancer growth. Yet, monotherapy to target the cyclin (CDK4/6) or the MEK pathway has often yielded disappointing results. Because co-alterations in cyclin and MEK pathway genes frequently co-occur, we hypothesized that resistance to CDK4/6 or MEK inhibitor monotherapy might be mediated via activation of oncogenic co-drivers, and that combination therapy might be useful. Patients and methods Herein, we describe nine patients with advanced malignancies harboring concomitant CDKN2A and/or CDKN2B alterations (up-regulate CDK4/6) along with KRAS or BRAF alterations (activate the MEK pathway) who were treated with palbociclib (CDK4/6 inhibitor) and trametinib (MEK inhibitor) combination-based regimens. Results Two patients (with pancreatic cancer) achieved a partial remission (PR) and, overall, five patients (56%) had clinical benefit (stable disease {greater than or equal to}6 months/PR) with progression-free survival of ~7, 9, 9, 11, and 17.5+ months. Interestingly, one of these patients whose cancer (gastrointestinal stromal tumor) had progressed on MEK targeting did well for about one year after palbociclib was added. Conclusions These observations suggest that co-targeting cyclin and MEK signaling can be successful when tumors bear genomic co-alterations that activate both of these pathways. Further prospective studies using this matching precision strategy in order to overcome resistance are warranted.